Finally there’s research comparing the epigenetic marks of human brain neurons to those of other primates, and it’s found real differences that make us function in a unique way. Do these epigenetic modifications help give us the brainpower for reflection, sentience, sapience, consciousness, and so forth? I’m not a gambler, but since primate neuron-specific genes don’t show a whole lot of difference from one another in their protein-coding sequences, that’s where I’d put my money. If I really had to.
With only one study to look at so far, this line of inquiry is in its infancy, to be sure. No one else has looked at the epigenetic component of human brain evolution. Hennady Shulha, Jessica Crisci, and Schahram Akbarian at the University of Massachusetts Medical School — and colleagues — took that first step with research they published in PLoS Biology late last month.
[Update 12/20/2012: Twitter friend @ed vautier points me to this study in Epigenetics, which documents the evolution of additional CpGs in humans, compared to non-human primates, and looks at their relative methylation levels. It's not neuron-specific, but it's in the same bucket as this study, so I thought I'd note it here. And so I have. And there you have it.]
What they find is this: Human prefrontal cortex neurons sport 33 epigenetic modifications — histone H3 trimethylated at lysine 4, or H3K4me3 — in genomic locations where macaques and chimps are much less likely to feature them. These H3K4me3 marks tended to appear near each other, and when the research team used chromosome conformation capture to look more closely at the region around one gene, DPP10, they discovered that chromosome looping appears to allow two nearby H3K4me3 modifications to come into contact.
But although H3K4me3 marks often lead to higher gene expression levels, this interaction seems to cause down-regulation of DPP10 through an interesting mechanism. As it turns out, increased anti-sense DPP10 RNA might be the answer. When the team did RNA-seq and quantitative RT-PCR on cortex neuron samples from separate human subjects, they found high levels of DPP10‘s anti-sense RNA and lower levels of DPP10 sense mRNA, as compared to the analogous macaque and chimp neurons.
The team also found the anti-sense RNA at higher levels in the human subjects’ neuron-rich prefrontal cortex layers II-IV, but not in neuron-poor layer I, white matter, or cerebellar cortex.
What’s more, the researchers discovered that the sequence of anti-sense DPP10 RNA has GC-rich areas that could allow it to form a stem-loop structure to interact with Polycomb 2 and transcription start sites — qualities that would support the RNA’s role in regulation.
Now, there’s no disease known to result from any DPP10 epigenetic modifications. But the authors note that rare variants “confer strong genetic susceptibility to autism, while some of the gene’s more common variants contribute to a significant risk for bipolar disorder, schizophrenia, and asthma.” That is, it’s a pretty good candidate for a gene that affects cortex function: Also according to the authors, it encodes a dipeptidyl peptidase-related protein that regulates potassium channels and neuronal excitability.
(It goes beyond DPP10, too. Five other genes associated with some of the 33 human-specific H3K4me3 peaks have ties to psychiatric diseases.)
So does all this point to an epigenetic role in human brain evolution? It starts to look even more convincing, considering what the researchers report about genetic changes in the DNA around these H3K4me3 marks, since the DNA sequence might very well have an important influence on histone binding and other functions. Compared to macaques, chimps, gorillas, and orangutans, the human versions of these DNA sequences have undergone major changes, with nucleotide substitution rates of 2- to 5-fold.
Meanwhile, nearby protein-coding sequences remained relatively unchanged in humans, as compared with the other primates. Also, compared to our close hominid relatives Homo denisova and Neanderthals, the nucleotide substitution rate near human H3K4me3 is much lower — about half the rate that the comparisons with non-human primates revealed. So the authors speculate that …
Taken together, these results suggest that at least a subset of the TSS regions with H3K4me3 enrichment in human (compared to non-human primates) were exposed to evolutionary driven DNA sequence changes on a lineage of the common ancestor of H. sapiens and the archaic hominins, but subsequently were stabilized in more recent human evolution, after splitting from other hominins.
What I like about this research is that the team used real human brain cells. No, not from living people, of course. Cadavers. And they didn’t just grind up a lump of brain in the blender, either. They painstakingly separated prefrontal cortex neurons from glial cells and other types to get at the real differences in the cells that matter, from the brain region that makes executive decisions and fancy associations.
What’s more, they may have sidestepped the problem with dead tissue — sample degradation – by measuring histone methylation. Apparently these marks don’t appear to change much after their host has died.
What I don’t like about the study is pretty standard. The human brain samples came from only 11 subjects — seven children and four adults.
The research team focused only on H3K4me3 peaks that all the humans had in common, so although they might’ve missed some peaks, it’s not that bad of a shortcoming. But there’s also the problem that the human subjects’ brains had already developed — as the authors hint in their discussion, fetal neuronal gene regulation could hold many of the important secrets, since the period of actual brain development is when you’ll probably find a lot of human-specific differences.
I’m anxious to see more of these kinds of studies, and I bet they’re in the works right this minute. It seems that there’s finally a big enough set of lab tools to get at the nitty-gritty parts of big questions.
[Flickr user IsaacMao's picture "Child Brain" is used here under a Creative Commons license.]
Shulha HP, Crisci JL, Reshetov D, Tushir JS, Cheung I, Bharadwaj R, Chou HJ, Houston IB, Peter CJ, Mitchell AC, Yao WD, Myers RH, Chen JF, Preuss TM, Rogaev EI, Jensen JD, Weng Z, & Akbarian S (2012). Human-specific histone methylation signatures at transcription start sites in prefrontal neurons. PLoS biology, 10 (11) PMID: 23185133